3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine derivatives (formula II):
are disclosed in EP 1140893 B1 and U.S. Pat. No. 6,596,758 patents as intermediates for the preparation of 5-(3,3-dimethyl-2,3-dihydro benzoxepin-5-yl)-2,4-pentadienoic acid derivatives useful for treating dyslipidemias, athero-sclerosis and diabetes.
In these patents, compounds of formula II are prepared according to the following scheme:

This synthetic method involves four chemical steps starting from benzoxepinone and the yields, as reported, are moderate.
Furthermore, this synthetic pathway cannot be easily scaled up to commercial implementation.
It now has been found a novel improved synthetic route for preparing the compounds of formula (II) which is unexpectedly applicable at industrial scale.
Advantageously, the compounds of formula (II) can be obtained in only three steps, each being characterized by high yields.
As another advantage, the invention provides an economical and efficient route for preparing the compounds of formula (II).
According to the present invention, compounds of formula (II) are prepared from new compounds of formula (I):
Thus, in one aspect, the present invention is related to compounds of general formula (I):

Each of R is independently chosen from a halogen atom; a cyano group; a nitro group; a carboxy group; an optionally halogenated (C1-C18)alkoxycarbonyl group; an Ra—CO—NH— or RaRbN—CO— group [in which Ra and Rb independently represent optionally halogenated (C1-C18)alkyl; a hydrogen atom; (C6-C10)aryl or (C6-C10)aryl(C1-C5)alkyl (where the aryl parts are optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl group or by an optionally halogenated (C1-C5)alkoxy group); (C3-C12)cycloalkyl optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl group or by an optionally halogenated (C1-C5)alkoxy group]; an optionally halogenated (C1-C18)alkyl group; optionally halogenated (C1-C18)alkoxy; and (C6-C10)aryl, (C6-C10)aryl(C1-C5)alkyl, (C6-C10)aryloxy, (C3-C12)cyclo-alkyl, (C3-C12)cycloalkenyl, (C3-C12)cycloalkyloxy, (C3-C12)cycloalkenyloxy; (C6-C10)aryloxycarbonyl or (C6-C10)arylcarbonyl; in which the aryl, cycloalkyl and cycloalkenyl parts are optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl or by an optionally halogenated (C1-C5)alkoxy;
p represents 0, 1, 2, 3 or 4;
R1 and R2 are a (C1-C18)alkyl group or form together —(CH2)n— wherein n represents 2, 3 or 4.
The formula (I) encompasses all types of geometric isomers and stereoisomers of the compounds of formula (I).
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched, having 1 to 18 carbon atoms in the chain. Preferred alkyl groups have 1 to 12 carbon atoms in the chain.
“Branched alkyl” means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
“Lower alkyl” means an alkyl group with 1 to about 4 carbon atoms in the chain which may be straight or branched.
Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
The alkyl group may be substituted by one or more halogen atoms representing thus an “halogenoalkyl” group.
“Halogen atoms” means fluorine, chlorine, bromine or iodine atoms. Preferred are fluorine, chlorine or bromine atoms and more preferred is fluorine atoms.
The “halogenoalkyl” groups may thus refer to “perfluoroalkyl”, which means groups corresponding to the formula “—CnF2n+1” wherein n represents 1 to 18.
Examples of perfluoroalkyl groups are pentafluoroethyl or trifluoro-methyl.
“Alkoxy” means an alkyl-O— group wherein the alkyl group is as herein described. Exemplary alkoxy groups include methoxy, ethoxy, isopropyloxy, butoxy and hexyloxy radicals.
“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system of about 3 to 12 carbon atoms. Preferred ring sizes of the ring system include about 3 to 8 and more preferably 5 to 6 ring atoms. The cycloalkyl is optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Exemplary monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.
Exemplary multicyclic cycloalkyl include 1-decalyn, norbornyl and the like.
“Cycloalkenyl” means a non-aromatic mono- or multicyclic ring system of about 3 to about 12 carbon atoms, preferably of about 5 to about 10 carbon atoms, and which contain at least one carbon-carbon double bond.
Preferred ring size of rings of the ring system include about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Exemplary monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. An exemplary multicyclic cycloalkenyl is norbornylenyl.
“Aryl” means an aromatic monocyclic or multicyclic ring system of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more “ring system substituents” which may be the same or different and are as defined herein. Exemplary aryl groups include phenyl or naphtyl, or substituted phenyl or substituted naphtyl.
“Alkenyl” means an aliphatic hydrocarbon group containing one or more carbon-carbon double bond and which may be straight or branched, having about 2 to about 12 carbon atoms in the chain, and more preferably about 2 to about 4 carbon atoms in the chain.
“Branched alkenyl” means that one or more lower alkyl or alkenyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group may be substituted by one or more halogen atoms. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexyl-butenyl and decenyl.
“Aryloxy” means an aryl-O— group wherein the aryl group is as defined herein. Exemplary groups include phenoxy and 2-naphtyloxy.
“Aryloxycarbonyl” means an aryl-O—CO— group wherein the aryl group is as defined herein. Exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphtoxycarbonyl.
“Arylcarbonyl” refers to an aryl-CO— group wherein the aryl group is as defined herein.
Exemplary arylcarbonyl group includes benzoyl.
The (C6-C10) aryl, (C3-C12) cycloalkyl, (C3-C12) cycloalkenyl are optionally substituted by one or more “ring system substituents”.
“Ring system substituents” mean substituents attached to aromatic or non-aromatic ring systems, inclusive of halogen atoms, an optionally halogenated (C1-C5) alkyl, or an optionally halogenated (C1-C5)alkoxy, halogen, alkyl and alkoxy being as defined herein,
The wording “in which the aryl, cycloalkyl and cycloalkenyl parts are optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl or by an optionally halogenated (C1-C5)alkoxy” means that the aryl, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more substituents selected from the group consisting of:                halogen atoms;        alkyl groups optionally substituted by one or more halogen atoms, and        alkoxy groups optionally substituted by one or more halogen atoms.        
The wording “optionally halogenated” means, in the context of the description, optionally substituted by one or more halogen atoms.
Preferably, each of R independently represents a halogen atom, an optionally substituted halogenated (C6-C10) arylcarbonyl, an optionally halogenated (C1-C18) alkyl, an optionally halogenated (C1-C18) alkoxy, or an optionally halogenated (C6-C10) aryl.
More preferably, R represents a (C1-C18) alkoxy group, more preferably a (C1-C4) alkoxy group and, most preferably, a methoxy group.
Preferably, p is 1 or 2 and more preferably 1.
R may be located in ortho (6), meta (3 or 5) and para (4) position on the phenyl ring with regard to the methoxy ethenyl group, preferably in meta position, more preferably at position 5.
Preferably, R1 and R2 represent independently a (C1-C4) alkyl group, and more preferably methyl, ethyl or isopropyl.
In another preferred embodiment, R1 and R2 form together a —(CH2)n— chain in which n represents 2 or 3.
According to the invention, a preferred embodiment is the compound of formula (I) in which R1 and R2 both represent a C2H5— group or form together a —CH2—CH2— group.
Preferred compounds of formula (I) can be selected from the group consisting in:    1) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-bromo-phenyl)-ethene    2) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-3-methoxy-phenyl)-ethene    3) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-4,5-dichloro-phenyl)-ethene    4) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-fluoro-phenyl)-ethene    5) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-(para-chlorobenzoyl)-phenyl)-ethene    6) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-trifluoro-methyl-phenyl)-ethene    7) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-fluoro-2-phenyl)-ethene    8) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-chloro-phenyl)-ethene    9) E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-4,5-dimethoxy-phenyl)-ethene    10)E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-phenyl-phenyl)-ethene    11)E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy)-phenyl)-ethene    12)E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-methoxy-phenyl)-ethene.    13)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-bromo-phenyl)-ethene    14)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-3-methoxy-phenyl)-ethene    15)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-4,5-dichloro-phenyl)-ethene    16)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-fluoro-phenyl)-ethene    17)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-(para-chlorobenzoyl)-phenyl)-ethene    18)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-trifluoro-methyl-phenyl)-ethene    19)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-fluoro-2-phenyl)-ethene    20)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-chloro-phenyl)-ethene    21)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-4,5-dimethoxy-phenyl)-ethene    22)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-phenyl-phenyl)-ethene    23)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy)-phenyl)-ethene    24)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-methoxy-phenyl)-ethene.
According to a particularly advantageous embodiment of the invention, a preferred compounds is a compound in which R=5-OCH3,p=1 and R1 and R2 both form a —CH2—CH2— group (formula (IA)).

According to a particularly advantageous embodiment of the invention, a preferred compound is in which R=7-OCH3, p=1 and R1=R2=C2H5— (formula (IB)).
Method for Preparing Compounds of Formula (II) Starting from Compounds of Formula (I)
According to the invention, the compounds of formula (I) are used for the preparation of compounds of formula (II) according to scheme 2:

Thus, in another aspect, the present invention is directed to a method for preparing compounds of formula (II), comprising:
a) reacting the compound of formula (I) with an acid; and optionally
b) isolating the obtained compound of formula (II).
The conversion of the compound of formula (I) into the compound of formula (II) is carried out in the presence of an acid. The acid acts as a catalyzing agent. There is no particular restriction on the nature of the acid used in this reaction and any acid conventionally used in a reaction of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule.
Suitable acids for catalyzing the cyclization reaction in step i) include inorganic acids such as chlorhydric acid, sulfuric acid, nitric acid and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethane-sulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
Inorganic acids are most preferred, and notably sulfuric acid.
The amount of acid is for example 0.2 to 2 moles and more preferably 0.5 to 1 moles relative to 1 mole of compound (I).
There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagent involved.
Suitable solvents for step a) are polar and aprotic solvents such as acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO), DMF being particularly preferred.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it has been found convenient to carry out the reaction at a temperature from about room temperature to about 100° C. and preferably from about 50° C. to 100° C.
The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period from about 3 hours to about 20 hours will usually be sufficient.
The compounds thus prepared may be recovered from the reaction mixture by conventional means, for example the compounds may be recovered by distilling of the solvent from the reaction mixture or, if necessary, after distilling of the solvent from the reaction mixture, pouring the residue into water, followed by extraction with a water-immiscible organic solvent and distilling of the solvent from the extract. Additionally, the product can, if desired, be further purified by various well known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
Preferred compounds of formula (II) which may conveniently be prepared staring from corresponding compounds of formula (I) according to the present invention can be chosen from the group consisting in:
3,3-dimethyl-5-formyl-7-bromo-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-9-methoxy-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7,8-dichloro-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-fluoro-8-chloro-2,3-di-hydrobenzoxepine,
3,3-dimethyl-5-formyl-7-(para-chlorobenzoyl)-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-trifluoromethyl-2,3-di-hydrobenzoxepine,
3,3-dimethyl-5-formyl-7-fluoro-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-chloro-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7,8-dimethoxy-2,3-dihydro-benzoxepine,
3,3-dimethyl-5-formyl-7-phenyl-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-methoxy-2,3-dihydrobenzoxepine.
Method for Preparing the Compounds of Formula (I)
The compounds useful according to the invention may be prepared by the application or adaptation of known methods, by which are meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989.
In another aspect, the invention relates to a method for preparing the compound of formula (I) comprising:                ii) reacting an aldehyde (V) resulting from step i) with a phosphorus ylid prepared from the reaction of a phosphonate (XIIa) or phosphonium salt (XIIb) with a base,        
                T1 and T2 represent independently (C1-C5) alkyl, T3, T4, T5 represent independently (C1-C5) alkyl or (C6-C10) aryl, and optionally        iii) isolating the obtained compound of formula (I).        
Preferably, the aldehyde (V) is prepared by:                i) reacting a compound of formula (III) with a compound of formula (IV) in the presence of a base        
                wherein R, R1, R2 and p are as defined hereabove, X represents an halogen atom, a (C6-C10) arylsulfonyloxy, a (C1-C6) alkylsulfonyloxy.        
“Arylsulfonyloxy” means an aryl-SO2— group wherein the group aryl is as defined herein. Examples of arylsulfonyloxy groups include the tosyl group of formula p-CH3(C6H5)—SO3—.
“Alkylsulfonyloxy” means an alkyl-SO2— group wherein the group alkyl is as defined herein. Examples of alkylsulfonyloxy group include the mesyl group of formula CH3—SO3—.
This synthetic route is illustrated in scheme 3:
Step i)
The reaction of step i) is carried out in the presence of a base. There is no particular restriction on the nature of the base to be used in this reaction, and any base conventionally used in reactions of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule.
Examples of suitable basis include alkali metal hydrides such as sodium hydride and potassium hydride; (C1-C10) alkyllithium compounds such as methyllithium and butyllithium, and alkali metal alkoxides, such as sodium methoxide and sodium ethoxide, and alkali metal carbonates, such as potassium carbonate and sodium carbonate. Of these, the alkali metal carbonates are particularly preferred.
The amount of base is for example 2 to 10 moles and preferably 2 to 3 moles relative to 1 mole of compound III.
There is no particular restriction on the nature of the solvent to be used, provided that is has no adverse effect on the reaction or on the reagent involved.
Examples of suitable solvents include hydrocarbons, which may be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, benzene, toluene and xylene; aprotic polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide. Of these, toluene, N-methylpyrrolidone, dimethylformamide and dimethylsulfoxide are particularly preferred.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it has been found convenient to carry out the reaction at a temperature of from about room temperature (20° C.) to 150° C., and more preferably of from 50° C. to 100° C.
The molar ratio of compound (IV) relative to compound (III) may vary from 1.0 to 1.5 equivalent, preferably from 1.05 to 1.1.
Step ii)
The reaction implemented in stage ii) is either a Wittig reaction or a Horner-Emmons/Wadsworth-Emmons reaction. These reactions are both well-known in the art and typically involve the preparation of a reactive ylid. For any further information on that subject, reference may be made to G. Wittig, U. Schöllkopf, Ber. 87, 1318 (1954); G. Wittig, W. Haag, ibid. 88, 1654 (1955); L. Horner et al., Ber. 91, 61 (1958); idem et al., ibid. 92, 2499 (1959); W. S. Wadsworth, Jr., W. D. Emmons, J. Am. Chem. Soc. 83, 1733 (1961).
When the ylid is prepared from a phosphonium salt (compound XIIb), the reaction implemented is a Wittig reaction.
When the ylid is prepared from a phosphonate (compound XIIa), the reaction is called a Horner-Emmons or Wadsworth-Emmons reaction.
At stage ii), the ylid is prepared by reacting a base either with a compound (XIIa) or with a compound (XIIb). The base used has to be sufficiently strong to remove an hydrogen atom in the alpha-position of the phosphorus.
Typically, the base is selected from the group consisting of alkali metal hydrides, alkali metal carbonates, alkali metal amides, (C1-C10) alkyllithium, and alkali metal alkoxides.
In the context of the invention, alkali metal hydrides such as sodium hydride and potassium hydride, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide are particularly preferred.
The reaction of the base on the compounds (XIIa) or (XIIb) is effected in a solution, preferably in an aprotic solvent, and notably in a solvent able to dissolve the phosphonate (XIIa) and respectively the phosphonium salt (XIIb).
Examples of suitable solvents are notably aprotic solvents, such as aromatic hydrocarbons, as for example benzene and toluene, ethers, such as diethylether, dioxane or tetrahydrofuran; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or HMPT and mixtures thereof.
The reaction of step ii) can take place over a wide range of temperatures, depending on the acidity of the compound (XIIa), respectively (XIIb), which means the ability to remove the hydrogen atom on the alpha-position with regard to the phosphorus. The type of the base used directly influences the choice of the reaction temperature. Thus, the stronger the base is, the lower the reaction temperature is.
When the base is an alkali metal alkoxide, a temperature comprised between −10° and 100° C. is generally suitable.
A stoichometric amount of basis is generally required in step ii) to convert the phosphonate or the phosphonium salt into the corresponding ylid. However, a slight excess of base may be used to ensure the total conversion of the compounds (XIIa) or (XIIb) into the ylid. Thus, the molar ratio of the base relative to the compound (XIIa), respectively (XIIb), is maintained between 1 and 1.2, preferably between 1 and 1.1, and more preferably between 1 and 1.05. The concentration of the compound (XIIa), respectively (XIIb), in the reaction mixture is not critical according to the invention. The concentration may vary between 0.01 mol/L and 10 mol/L, preferably between 0.1 and 1 mol/L.
According to a preferred embodiment, the ylid resulting from the reaction of the compound (XIIa), respectively (XIIb), with a base is performed before adding the aldehyde (V).
Preferably, the phosphorus ylid is prepared from a phosphonium salt (XIIb), more preferably from CH3OCH2PPh3Cl.
According to a preferred embodiment, the ylid is prepared by reacting CH3OCH2PPh3Cl with potassium tert-butoxide in tetrahydrofuran.
Compounds of Formula (IV)
In another aspect, the invention relates to compounds of formula (IV):
wherein X represents an halogen atom, a (C1-C6) alkylsulfonyloxy or a (C6-C10) arylsulfonyloxy,R1, R2 are a (C1-C18) alkyl group or form together a —(CH2)n—, wherein n represents 2, 3 or 4,with the exclusion of the compounds of formula (IV), wherein X═I and R1═R2═CH3; X═I, Br or pCH3—(C6H5)SO3—, and R1 and R2 form together a —(CH2)3— chain.
Preferred compounds of formula (IV) are notably those wherein
—R1, R2 represents a (C2-C6) alkyl group or form together a —(CH2)2— or —(CH2)4— chain; and/or
—X represents Cl, Br, I or CH3SO3—.
Most preferred compounds are notably the compounds of formula (IV) wherein:
X represents Cl, Br, I, CH3SO3— and/or R1═R2═C2H5 or R1 and R2 form together a —(CH2)2— chain.
The compounds of formula (IV) are particularly useful for preparing the compounds of formula (I) and, as a result, are also advantageous synthetic intermediates for the preparation of the compounds of formula (II).
Step iii)
The compounds of formula (I) thus prepared may be recovered from the reaction mixture by conventional means, for example the compounds may be recovered by distilling of the solvent from the reaction mixture or, if necessary, after distilling of the solvent from the reaction mixture, pouring the residue into water, followed by extraction with a water-immiscible organic solvent and distilling of the solvent from the extract. Additionally, the product can, if desired, be further purified by various well known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
Methods for Preparing of the Compound of Formula (IV)
The compounds of formula (IV) according to the present invention may be prepared by the application or adaptation of known methods, by which are meant methods used heretofore or described in the literature, for example those described by R. C Larock in Comprehensive Organic Transformations, VCH Publishers, 1989.
In another aspect, the invention is directed to a method for preparing the compound of formula (IV).
The compound of formula (IV) may be prepared by the method comprising the steps of:                b1) reacting an aldehyde (VIl) with alcohols R1OH and R2OH or HO—(CH2)n—OH, in the presence of an acid, wherein n, R1 and R2 are as defined hereabove;        
                and optionally        c1) isolating the resulting compound (IV).        
Preferably, the aldehyde (VII) is prepared by:                a1) oxidizing an alcohol of formula (VI) into the corresponding aldehyde (VII);        

wherein X represents an halogen atom, a (C6-C10) arylsulfonyloxy group, a (C1-C6) alkylsulfonyloxy group.
Step a1)
Conventional oxidizing agents may be used in accordance with standard practice to convert primary alcohols into aldehydes. Precautions must however be taken so that the aldehyde is not further oxidized to the carboxylic acid. For further information on that subject, reference may be made to March's, Advanced Organic Chemistry, Michael B. Smith and Jerry March.
Suitable oxidizing agents include DMSO, chromate salts such as pyridinium dichromate, Na2Cr2O7, K2Cr2O7, Cr3 and NCS/tempo and tempo/NaOCl.
Different solvents may be used provided that they have no adverse effect on the reaction or on the reagent involved.
Examples of suitable solvents are notably halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform.
According to a preferred embodiment, the alcohol (VI) is oxidized by tempo/NaOCl in dichloromethane, in similar conditions than those disclosed in the publication J. Jurczak et al., Tetrahedron (1998), vol. 54, p. 6051-6064.
Preferably, the group X of the compound (VI) represents a iodine atom.
Such compounds may be prepared from the corresponding compound of formula (IV), wherein X=Cl, Br or alkylsulfonyloxy, according to conventional methods,.
As an example, the compound of formula (VI), wherein X=Cl, may be converted into X=I in the presence of NaI in DMF.
Step b1)
The acids which can be used in step b1) may be any conventional acid used for the protection of aldehydes under the form of a ketal.
Suitable acids include notably chlorhydric acid, sulfuric acid, nitric acid and phosphoric acid ; sulfonic acids such as methan sulfonic acid, ethane sulfonic acid, benzene sulfonic acid and paratoluene sulfonic acid. Of these, sulfonic acid and notably paratoluene sulfonic acid are particularly preferred.
The molar ratio of acid is for example 0.001 to 0.5 equivalents, more preferably 0.01 to 0.1 equivalents relative to the aldehyde VII.
The molar ratio of the alcohols R1OH and R2OH, or HO—(CH2)n—OH may vary from 1.0 to 2.0 equivalents relative to the aldehyde VII, more preferably from 1.0 to 1.1 inclusive.
In a preferred embodiment, the alcohol is HO—(CH2)n—OH, and more preferably ethylene glycol.
As an example, this preferred embodiment of preparation is illustrated by the preparation of the compound (IVA) according to scheme 5.

The compounds of formula (IV) may also be prepared by the method comprising the steps of:
a2) reacting an aldehyde of formula (VIII) with a formaldehyde of formula (IX) in the presence of a base and an acid;

b2) converting the alcohol function of the compound (X) into an halogen atom or a (C1-C16) alkylsulfonyloxy group or a (C6-C10) arylsulfonyloxy group; and optionally
c2) isolating the product obtained.

Step a2)
The preparation of compounds (X) in step a2) may be effected according to Tsuzuki et al., Tetrahedron Letters, Vol. 19, No. 11, p. 989-992 (1978) and Matsuda et al., Tetrahedron (46(10), p. 3469-3488, (1990)). Analogues have been described by L. Paquette et al. (JACS 105(25), p. 7352-7358, (1983 )) and by M. H. Seo et al. (J. of Korean Chem. Soc., 39(6), p. 489-491 (1995).
Step b2)
The reaction of step b2) may be effected according to conventional methods.
Preferably, the hydroxyl group of the compound (X) is converted into an alkylsulfonyloxy or arylsulfonyloxy group.
This conversion may be effected according to conventional methods such as reacting the compound (X) with an alkylsulfonyl or arylsulfonyl halide in the presence of a base.
Examples of suitable alkylsulfonyl or arylsulfonyl halides include notably alkyl or arylsulfonyl chloride or bromide such as methylsulfonyl chloride or p-toluenesulfonylchloride.
Examples of suitable bases include notably amines, preferably tertiary amines such as triethylamine, diisopropylethylamine.
Examples of suitable solvents include aprotic solvents, notably halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane.
This conversion of the hydroxyl group into an alkyl or arylsulfonyloxy group can take place over a wide range of temperatures, notably between −10° C. and 100° C.
According to a preferred embodiment, the alkylsulfonyloxy or arylsulfonyloxy group is converted into an halogen atom.
Conventional methods may be used such as reacting the alkylsulfonyloxy or arylsulfonyloxy group with an alkali metal halide such as sodium iodide, sodium bromide, lithium chloride.
Suitable solvents for this reaction are notably aprotic solvents, in particular aprotic polar solvents such as N,N-dimethylformamide, N-dimethylsulfoxide acetonitrile.
As an example, this synthetic route is illustrated by the preparation of compound (IVA) in the following scheme 6.

Alternatively, the hydroxyl function of the compound (X) may be converted directly into an halogen atom, according to conventional methods.
Conventional methods include notably reacting the alcohol (X) with the Me3SiCl in DMSO, or PPh3 in combination with CCl4 or CBr4.
For any further information regarding these methods, reference may be made to M. B. Smith and J. March, in March's Advanced Organic Chemistry, 5th edition, Wiley Interscience.
In the reactions described hereabove, it may be necessary to protect reactive functional groups, for example amino or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for example see T. W. Green and P. G. M. Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991; J. F. W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.
The starting materials are commercially available or may be prepared by the application or adaptation of known methods.
The compounds of the invention, their methods of preparation will appear more clearly form the examination of the following examples, which are presented as an illustration only and are not to be considered as limiting the invention in its scope.